ALPHA SYNUCLEIN IN MODELS OF MSA

多系统萎缩（MSA）的主要病理特征是少突胶质细胞中的胶质细胞胞浆包涵体（GCI）。GCI的主要成分是α-突触核蛋白。在一系列的研究中，将在过表达α-突触核蛋白的转基因（tg）小鼠品系中进行，我们将检查似乎有助于α-突触核蛋白积累和聚集的因素。具体目标1。我们假设在某些神经启动子控制下过表达h[alpha]-突触核蛋白的tg小鼠将在少突胶质细胞和/或神经元中积累h[alpha]-突触核蛋白，并可能导致GCI样改变的形成。我们已经建立了一个TG小鼠系，其中h[alpha]-突触核蛋白是 在血小板衍生生长因子B（PDGF-B）启动子的控制下过表达，并且这些tg小鼠表现出运动缺陷和h[α]-突触核蛋白在少突胶质细胞和神经元中的积累。我们已经建立了一个tg小鼠系，其中通过将h[alpha]-突触核蛋白转基因置于髓鞘碱性蛋白（MBP）启动子的控制下，α-突触核蛋白被靶向仅在少突胶质细胞中过表达。两种tg小鼠都将接受详细的行为、神经化学和神经病理学分析。具体目标2。我们假设氧化应激有利于h[alpha]-突触核蛋白的积累。为了研究这些因素的影响，将两种tg h[alpha]-突触核蛋白小鼠品系与超氧化物歧化酶（SOD）1、SOD 2和谷胱甘肽过氧化物酶敲除小鼠杂交。动物将按照特定目标1进行分析。具体目标3。我们假设硝化作用有利于h[alpha]-突触核蛋白的积累。为了研究这些因素的影响，将两种tg h[alpha]-突触核蛋白小鼠品系与神经元型一氧化氮合酶（nNOS）和诱导型NOS（iNOS）敲除小鼠杂交。动物将按照特定目标1进行分析。

The cardinal pathological feature of multiple system atrophy (MSA) is the glial cytoplasmic inclusion (GCI), which is found in oligodendrocytes. A major component of the GCI is alpha-synuclein. In a series of studies, which will be carried out in transgenic (tg) mouse lines overexpressing alpha-synuclein, we will examine factors that appear to contribute to the accumulation and aggregation of alpha-synuclein. Specific Aim 1. We hypothesize those tg mice overexpressing h[alpha]-synuclein under the control of certain neural promoters will accumulate h[alpha]-synuclein in oligodendrocytes and/or neurons and may result in formation of GCI-like alterations. We have established a tg mouse line, in which h[alpha]-synuclein is overexpressed under the control of the platelet-derived growth factor B (PDGF-B) promoter, and these tg mice demonstrate motoric deficits and accumulation of h[alpha]-synuclein in oligodendrocytes and neurons. We have established a tg mouse line in which alpha-synuclein is targeted to be overexpressed in only oligodendrocytes by placing the h[alpha]-synuclein transgene under the control of the myelin basic protein (MBP) promoter. Both strains of tg mice will undergo detailed behavioral, neurochemical and neuropathological analyses. Specific Aim 2. We hypothesize that oxidative stress favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with superoxide dismutase (SOD) 1, SOD 2 and glutathione peroxidase knockout mice. The animals will undergo analyses as in Specific Aim 1. Specific Aim 3. We hypothesize that nitration favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) knockout mice. The animals will undergo analyses as in Specific Aim 1.